Approximately 1.7 million people in the United States met diagnostic criteria for prescription opioid abuse or dependence in 2007 and more than 2 million people initiated misuse of these medications in the last three years of the National Survey of Drug Use and Health. Given that opioid addiction is known to be chronic and relapsing and cause individual and societal public health problems (individual morbidity and mortality, increased transmission of infectious diseases, and crime), more efficacious treatment options for this disorder are needed. Currently approved maintenance medications for opioid dependence, while efficacious, have been hampered by limited patient acceptance (naltrexone), limited availability (methadone), and concerns about diversion (methadone and buprenorphine). Tramadol, an atypical analgesic with opioid agonist activity that is uncontrolled by the Controlled Substances Act, has reduced abuse potential relative to other full mu- opioid agonists and may be an effective treatment for opioid dependence. This two-week randomized, placebo-controlled inpatient study has two phases, each with one primary aim. Phase 1 (Days 1-7) will evaluate the withdrawal suppression efficacy of extended release (ER) tramadol for treatment of short-acting prescription opioid withdrawal. Phase 2 (Days 8-14) will assess the characteristics and severity of withdrawal from acute cessation of ER tramadol dosing and will provide further information about the strength of opioid agonist effects and dependence potential produced by tramadol. Persons age 18-55 years old with a positive observed opioid urine specimen, self-report of use of a short-acting opioid at least 21 out of the last 30 days, meeting diagnostic criteria for prescription opioid dependence (otherwise healthy) will be eligible for inpatient admission to the residential research unit. After the first overnight stay (to ensure a period of opioid abstinence), participants showing observable signs of opioid withdrawal will be randomized to one of three double-blind treatments: placebo or ER tramadol (400 or 800 mg daily given as two divided doses of matched capsules). Stratification will occur based on three levels of objective opioid withdrawal severity (low, medium, and high) as assessed by trained staff immediately prior to randomization. Twelve subjects will be needed to complete each treatment arm (n=36). Tramadol doses will be escalated over the first 24 hours to decrease chance of side effects. Ancillary medications are available to all groups to treat breakthrough withdrawal. Primary outcome measures include the participant-rated Opioid Adjectives Questionnaire Withdrawal Scale and amount of ancillary medication used for breakthrough opioid withdrawal during each Phase of the study. Numerous secondary outcome measures will be collected. The data gathered from this study will provide novel and important information regarding the dose-related withdrawal suppression efficacy of ER tramadol and determine whether tramadol produces a withdrawal syndrome after acute cessation. These results will be used to determine if a larger-scale evaluation of tramadol for prescription opioid dependence is warranted. PUBLIC HEALTH RELEVANCE: Prescription opioid addiction is a growing public health problem and more pharmacologic treatments are needed because current approved medications have had limited patient acceptance (naltrexone), limited availability (methadone), and concerns about misuse and diversion (methadone and buprenorphine). Tramadol is a currently approved medication used to treat moderate-severe pain, and initial studies demonstrate that it may be useful for treatment of the uncomfortable syndrome of opioid withdrawal without producing euphoric effects. This study will determine whether two different doses of extended release tramadol can treat opioid withdrawal and whether tramadol itself produces withdrawal after it is no longer taken.